Althouth diabetic patients are treated with insulin or hypoglycemic drugs, they develop with time a number of complications which severely affect the quality and length of life. A number of years ago we proposed that the nonenzymatic addition of glucose to vital proteins might be a unifying biochemical basis for these pathological events. The evaluation of this hypothesis has led to the development of hemoglobin A1c as a convenient measure of the integrated blood glucose over time and to the recognition that further rearrangements of nonenzymatic browning occurs in vivo on long-lifed proteins which are noted to be altered in diabetes and aging. Recent studies have shown that these brown pigments accumulate linearly with age in normal individuals on lens crystallins and dura collagen while diabetics accumulate significantly more. During the next grant period we will continue our studies on three long-lifed proteins-lens crystallin, collagen, and myelin of peripheral nerve. In brief, we plan to 1) determine the structure of two brown pigments that have recently been isolated; 2) isolate other brown pigments from aged proteins and model reactions; 3) develop new methods for measuring the amount of brown pigments in biological specimens; (4) determine the amount of brown pigments on a number of long-lifed proteins (e.g. myelin of the peripheral and central nervous systems, basement membrane); 5) assess factors that control the rate of browning in vivo; and 6) study the effect of brown pigments on the properties of these proteins which could account for the observed changes. These studies should advance our knowledge of the role of glycosylation and browning and give insight into pharmacological ways of preventing complications.